BIOAVAILABILITYE N H A N C E M E N T

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INTRODUCTION

In life-cycle management of

pharmaceutical products, novel drug

delivery technologies that offer positive

differentiation over first-generation

products provide an important means for

staying competitive in today’s business

environment. This article will briefly

discuss a proven and scalable solid

dispersion approach based on spray-drying

that is suitable for Biopharmaceutical

Classification System (BCS) (Figure 1)

Class II active pharmaceutical ingredients

(APIs) and new chemical entities

(NCEs).1-4

Many existing APIs and NCEs are

poorly water soluble and subsequently

have low oral bioavailability if formulated

in unmodified form. Traditional

approaches to overcoming this include (1)

improvement of water miscibility by

employing self-emulsification, lipid-based

techniques, solubilization into micellar

cores, or alternatively complexation with

cyclodextrins; (2) reduction of particle size

to nano-scale via mechanical milling or

high-shear processing accompanied by

particle stabilization; and (3) impacting

crystal lattice energy using polymorphs or

co-crystals, or through the creation of solid

dispersions of drug in inert carriers or

matrices.5-11

Increasingly, solid dispersions are

being looked at as a viable solution to this

pervasive issue. Although only a few solid

dispersions are currently marketed, the

approach has some inherent advantages

over other approaches. Presence of an

active compound as a molecular or nano-

particle dispersion combines the benefits

of decreasing crystal lattice energy and

maximizing surface area, thus facilitating

better contact with dissolution media.

Fortuitously, many of the carriers that can

be employed for the production of solid

dispersions are generally recognized as

safe (GRAS) and are already extensively

used as excipients in marketed products,

easing the regulatory burden.

Particle Sciences has developed

DOSETM a formulaic approach to dosage

form development that rapidly narrows in

A Novel Spray-Drying Technology to Improvethe Bioavailability of Biopharmaceutical Classification System Class II MoleculesBy: David Shi, PhD; Andrew Loxley, PhD; Robert W. Lee, PhD; and David Fairhurst, PhD

F I G U R E 1

on the drug delivery technology of choice.

When solid dispersions are called for, Particle

Sciences has a number of approaches, one of

these is a unique solid dispersion technology

based on spray-drying using a dual-polymer

system that significantly improves the

dissolution and bioavailability of poorly soluble

APIs. The technology has been proven in

human trials and has been scaled to

commercial levels. Under Particle Sciences

DOSE system, APIs are first extensively

characterized as to their physicochemical

characteristics, including a proprietary

solubility screen. Then after excipient

compatibility studies, formulation prototypes

are screened for their impact on solubility and

permeability. This methodical iterative

approach allows one to rapidly narrow in on

the formulation approaches most likely to yield

the desired results.

THE DRUG DELIVERY PROBLEM

An increasing number of compounds

coming out of discovery are poorly soluble.

By some estimates, 40% to 70% of new lead

compounds in development fall into this

category.12,13Additionally, many new

compounds also exhibit poor permeability. In

1993, the BCS was proposed as a way to

facilitate the marketing of generic drugs. The

system classifies a given compound by its

aqueous solubility and gut permeability.

Beyond its regulatory use, the BCS

provides a very useful framework in which to

evaluate APIs and chart a logical course to

achieve the desired pharmacokinetics (PK),

including greater bioavailability. For BCS II

and IV molecules, in which solubility is the

main or largely contributing limiting property,

there are a number of approaches, including

increasing surface area through particle size

reduction, surface morphology modification,

and solid solutions.

A NOVEL DUAL-POLYMER

SPRAY-DRYING SOLUTION

Generating human data as quickly as

possible is the goal of every drug developer,

and there are several philosophies as to how

best to achieve first in human (FIH) dosing. It

has been estimated that three to six formulation

changes occur from FIH to

commercialization.14At Particle Sciences, we

believe that FIH experience should be in a

formulation that will provide useful

developmental data. For a BCS I molecule, the

prototypical formulation could be a simple

powder-filled capsule. For a poorly water-

soluble molecule, BCS II or IV, such a simple

system is unlikely to provide any commercially

helpful data, speed development, or bring to

light clinically relevant findings. Therefore, an

FIH formulation designed to deliver the drug in

a commercially viable way is, in our view,

important. For drugs with limited aqueous

solubility, one such approach discussed in this

paper involves a patented dual-polymer system

utilizing GRAS excipients and traditional

processing techniques.

In this approach, the API is solubilized in

a water-miscible organic solvent, usually

ethanol. A mixture of an amphiphilic and a

hydrophilic polymer are prepared as a mixedDrug Development & Delivery January 2012 Vol 12 No 1

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aqueous solution. The organic API solution and

the aqueous polymer mixed solution are then

mixed under carefully controlled temperature

and agitation rate to form a transparent or hazy

solution, which is subsequently spray-dried.

The exact compositions of the feed stocks are

determined in an extensive, yet efficient,

preformulation phase utilizing Design of

Experiment (DoE) methodology, when

appropriate. Key drivers include the API’s

solubility in various organic solvents, the API’s

molecular weight, the solubilities of the

polymeric excipients, and the compatibility of

the API and polymeric excipients in the spray-

drying solution.

In the context of this technology,

amphiphilic polymers are defined as soluble

both in organic solvents and in water.

Examples of amphiphilic polymers suitable for

use include but are not limited to polyethylene

oxides (PEO, also commonly referred to as

polyethylene glycol or PEG), PEO derivatives,

PEO copolymers, such as PEO/polypropylene

glycol (PPG) copolymers, PEG-modified

starches, poloxamers, poloxamines,

polyvinylpyrrolidones, hydroxypropyl

cellulose, hypromellose, and esters thereof,

vinyl acetate/vinylpyrrolidone random

copolymers, polyacrylic acid, and

polyacrylates.

Hydrophilic polymers are defined as those

soluble in water or in a single-phase mixture of

organic solvent and water, but not soluble in

organic solvent alone. Examples of hydrophilic

polymers include but are not limited to starch,

sodium carboxymethylcellulose,

hydroxyethylcellulose, polyvinyl alcohol,

sodium alginate, chitosan, and carrageenan.

Notably, these formulations utilize only FDA-

approved polymers.

The use of hydrophilic polymers that

ionize at different pH allows for the design of

formulations targeted either to the stomach or

the intestine. For example, chitosan, which is

ionized at low pH, promotes drug release in the

stomach, while sodium carboxymethyl

cellulose and sodium alginate, ionized at

neutral conditions, facilitate release in the small

intestine.

The resulting powder is free flowing and

will contain 25% or more API. Characteristics

of the drug product include the following:

• Solubilized drug homogeneously

interwoven into a polymer matrix.

• Drug in crystalline form within the

polymer matrix.

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• Depressed API melting temperature and

enthalpy of fusion (Figure 1).

• Spontaneous formation of colloidal

dispersions upon contact with aqueous

media.

• Enhanced dissolution rate/solubility of

the drug in aqueous media as well as

prolonged supersaturation in relevant

biological fluids, and GI site-targeted

release of the drug.

CHARACTERIZATION

Powder X-ray diffraction (PXRD) is first

used to characterize the API powder and the

spray-dried formulation. As can be seen in

Figure 2, the model drug (Ibuprofen) shows

characteristic PXRD diffraction peaks, and a

drug product containing 25% of the API,

prepared by the novel dual-polymer spray-

drying approach also shows some of the these

same peaks, indicating that the API is present

in crystalline form. In contrast to some systems

that are dependent on amorphous API forms,

this technology results in very stable particle

constructs because the crystalline form of the

drug is the most thermodynamically favored

state.

In Figure 3, the impact of the technology

on melting temperature and enthalpy of fusion

is clearly demonstrated. It is believed that these

thermal property alterations are at least in part

responsible for the significant increase in

solubility provided by this technology.

Several commercial compounds have been

thoroughly evaluated using this novel

technology. Figure 4 shows the dissolution

profiles and clinical two-way pharmacokinetic

data for Resveratrol. Clearly, the rate of

dissolution is faster using the novel dual-

polymer spray-drying approach, and reaches a

higher final concentration than neat API.

Figure 5 shows clinical data showing

higher Cmaxand AUC for the novel spray-dried

resveratrol formulation in comparison with

neat API, indicating significant increases in

bioavailability when using this novel spray-

drying approach.

Figure 6 shows the dissolution profiles

and porcine pharmacokinetic data for

albendazole (A: dissolution profiles in 0.05 M

SLS of raw API and API product formulated

using the novel dual-polymer spray-drying

approach; B: dissolution profiles in fasted

simulated intestinal fluid of raw API and drug

product formulated using the novel dual-

polymer spray-drying approach; C: porcine PK

data for commercial product versus product

made by the novel dual-polymer spray-drying

approach; and D: efficacy in porcine model of

commercial product versus product made by

using the novel dual- polymer spray-drying

approach (data generated by Solubest, Ltd,

Israel). The API solubility is enhanced, PK data

are improved compared to a commercial

product, and efficacy in the animal model is

improved.

CONCLUSION

Whether reformulating an existing

compound or working with an NCE, the ability

to understand and manipulate those factors

within our control that dictate PK behavior is

key. For compounds with low solubility, we

have presented one approach to oral dosage

form development. Using GRAS ingredients

and a readily scaled and patented process,

employing this novel spray-drying technology

results in stable crystalline constructs that

increase API bioavailability by increasing the

solubility of the API. To date, the technology

has been demonstrated in more than a dozen

compounds and is currently being scaled for

Phase III for at least one. u

REFERENCES

1. Chen ML, Amidon GL, Benet LZ,

Lennernas H, Yu LX. The BCS, BDDCS,

and regulatory guidances. Pharm Res.

2011;28:2774.

2. Yu LX, Amidon GL, Polli JE, Zhao H,

Mehta MU, Conner DP, Shah VP, Lesko LJ,

Chen ML, Lee VH, Hussain AS.

F I G U R E 6

Drug Development & Delivery January 2012 Vol 12 No 1

xx

Biopharmaceutics classification system: the

scientific basis for biowaiver extensions.

Pharm Res. 2002;19:921.

3. Takagi T, Ramachandran C, Bermejo M,

Yamashita S, Yu LX, Amidon GL. A

provisional biopharmaceutical classification

of the top 200 oral drug products in the

United States, Great Britain, Spain, and

Japan. Mol Pharm. 2006;3:631.

4. Tsume Y, Amidon GL. The biowaiver

extension for BCS class III drugs: the effect

of dissolution rate on the bioequivalence of

BCS class III immediate-release drugs

predicted by computer simulation. Mol

Pharm. 2010;7:1235.

5. Kohli K, Chopra S, Dhar D, Arora S, Khar

RK. Self-emulsifying drug delivery

systems: an approach to enhance oral

bioavailability. Drug Discov Today.

2010;15:958.

6. Rahman MA, Harwansh R, Mirza MA,

Hussain MS, Hussain A. Oral lipid based

drug delivery system (LBDDS):

formulation, characterization and

application: a review. Curr Drug Deliv.

2011;8:330.

7. Kadam Y, Yerramilli U, Bahadur A, Bahadur

P. Micelles from PEO-PPO-PEO block

copolymers as nanocontainers for

solubilization of a poorly water soluble drug

hydrochlorothiazide. Colloids Surf B

Biointerfaces. 2011;83:49.

8. Kanwar JR, Long BM, Kanwar RK. The

use of cyclodextrins nanoparticles for oral

delivery. Curr Med Chem. 2011;18:2079.

9. Peltonen L, Hirvonen J. Pharmaceutical

nanocrystals by nanomilling: critical process

parameters, particle fracturing, and

stabilization methods. J Pharm Pharmacol.

2010;62:1569.

10. Miroshnyk I, Mirza S, Sandler N.

Pharmaceutical co-crystals-an opportunity

for drug product enhancement. Expert

Opin Drug Deliv. 2009;6:333.

11. Janssens S, Van den Mooter G. Review:

physical chemistry of solid dispersions. J

Pharm Pharmacol. 2009;61:1571.

12. Hauss DJ. Oral lipid-based formulations.

Adv Drug Deliv Rev. 2007;59:667.

13. Dubin CH. Formulation strategy for poorly

soluble drugs. Drug Del Technol.

2006;6:34.

14. Hussain AS. Quality by Design:

Integration of prior knowledge and

pharmaceutical development into CMC

submission and review: FDA Perspective.

AAPS Workshop; 2005.

Dr. David Shi, as a Polymer Scientist with a PhD in Polymer Chemistry, has

more than 15 years experience in development of new materials and drug delivery

systems for bio/medical applications. He joined Particle Sciences, a contract

research organization in Bethlehem, PA, as Formulation Scientist in 2009. He

specializes in pharmaceutical formulation development and drug delivery

technologies. In the past 10 years, his research has been focused on improving

drug delivery in oral, topical, inhalation, and injectable dosage forms. His

expertise includes nanoencapsulation, microencapsulation, liposomes, spray-

drying, and organic and polymer synthesis. Dr. Shi is co-inventor of 10 issued patents related to novel

drug delivery systems, some of which have been licensed, and has authored several peer-reviewed

journal articles.

Dr. Andrew Loxley is Director of New Technologies at Particles Sciences Inc., a

contract research organization in Bethlehem, PA, specializing in pharmaceutical

formulation development. He leads a variety of projects, based on novel and

proprietary nanotechnologies and combination devices, in fields from HIV vaccine

and microbicide development, to gene-silencing SiRNA delivery. Prior to joining

Particles Sciences, he led development efforts in next-generation lithium ion

batteries at A123 Systems Inc, electrophoretic displays at EINK Corp., and

emulsion polymers at Synthomer Ltd. British-born, he earned his BSc in Chemistry from the Univeristy

of Sussex and his PhD in Physical Chemistry focusing on microencapsulation from the University of

Bristol.

Dr. Robert W. Lee is Vice President of Pharmaceutical Development at Particle

Sciences Inc. He is responsible for product development as well as providing

support to clinical manufacturing operations and business development. His

responsibilities include oversight of formulation development, drug delivery,

analytical sciences, quality control, and quality assurance. Before joining Particle

Sciences, Dr. Lee held senior management positions at Novavax, Inc., Lyotropic

Therapeutics, Inc., and Imcor Pharmaceutical Co. He has also been in research

positions at élan Drug Delivery, NanoSystems, and Sterling Winthrop. Dr. Lee holds bachelors in

Biology and Chemistry from the University of Washington and a PhD in Physical Bioorganic Chemistry

from the University of California-Santa Barbara. He has published articles in numerous peer-reviewed

journals and three book chapters plus holds 11 issued patents and 14 provisional or PCT patent

applications. Dr. Lee has more than 20 years of experience in pharmaceutical research and

development of both therapeutic drugs and diagnostic imaging agents. He maintains strong academic

ties, including an appointment as Adjunct Associate Professor of Pharmaceutical Chemistry at the

University of Kansas in 1992, and serving as a reviewer for both the International Journal of

Pharmaceutics and Journal of Pharmaceutical Sciences and Editorial Advisory Board member for Drug

Development & Delivery.

Dr. David Fairhurst is Corporate Research Fellow at Particle Sciences Inc. He

earned his PhD in Physical Chemistry in 1968 from Liverpool Polytechnic, UK,

where he was also a Lecturer (in Physical Chemistry) for 4 years. He spent 2 years

as a Visiting Associate Professor in the Center for Surface and Coatings Research

at Lehigh University and subsequently held senior research positions with the UK

Chemical Defense Establishment, Porton Down, and with Union Carbide

Corporation, USA. The work encompassed exploratory and basic research, product

formulations, and development and technical services. He has spent the past 40 years in using colloid

and surface chemistry to solve problems in industrial and pharmaceutical applications and has

published more than 100 technical papers, scientific articles, and book chapters in the open

literature. Prior to joining PSI in 1993, he was, for 7 years, Director of Applications at Brookhaven

Instruments Corporation and is an internationally recognized authority on dispersion and emulsion

technology and in the assessment and characterization of particle size.

B I O G R A P H I E S